JP2020534362A - 成人における焦点てんかんの処置のための合成経皮的カンナビジオール - Google Patents
成人における焦点てんかんの処置のための合成経皮的カンナビジオール Download PDFInfo
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Abstract
Description
本出願は、2017年9月19日出願の米国仮特許出願公開第62/560,446号明細書、2017年12月1日出願の第62/593,575号明細書、2018年1月3日出願の第62/613,160号明細書、2018年4月5日出願の第62/652,995号明細書、及び2018年4月19日出願の第62/660,198号明細書の利益及び該明細書に対する優先権を主張する。それらの各々の全体的な内容は、それらの全体が参照により本明細書に組み込まれる。
SF28=(D日間の発作総数)×(28/D)
によって計算され、
式中、Dは、発作情報が指定の時間間隔について収集された全日数とする。
RedSF=SF28(ベースライン)−SF28(維持)
と定義する。
%RedSF=100×[SF28(ベースライン)−SF28(維持)/SF28(ベースライン)
と定義する。
STAR1(てんかんの処置のための合成経皮的カンナビジオール)と称して、カンナビジオールを評価する第2相無作為化二重盲検偽薬制御試験であって、焦点てんかんに罹患している成人へ、BID(1日2回)を12週間(維持期)投与する試験を行った。8週間のベースライン(ベースライン期)に続いて、患者を分割された用量(例えば、195mgを1日2回)の1日390mgのCBD、分割された用量(例えば、97.5mgを1日2回)の1日195mgのCBD、又は偽薬へ1:1:1に無作為化した。分割された日用量を12時間(±2時間)ごとに与えた。CBD経皮ゲルの及び偽薬を左右の両肩及び/又は両方の上腕に、該領域が乾燥するまで擦り込んだ。主要評価項目は、ベースラインに対する処置期間全体にわたる発作頻度の変化とした。主要評価項目は、ベースライン期を維持期と比較する、28日間当たりの発作頻度(SF28)における低減に基づいている。
患者(N=188)をSTAR1へ無作為化した。平均年齢は、39(18〜71)歳であった。ベースラインで、患者は、平均2.5の抗てんかん薬(AED)を服用しており、毎月の発作の中央値は10.6(3〜330)であった。群ごとで、ベースラインにおける毎月の発作頻度の中央値は、偽薬群については10.5、分割された用量群においては195mgの日用量から14.0、分割された用量群においては390mgについて10.14であった。
図1に関して、12週間の盲検処置後、焦点起始発作の低減の中央値は、195mg/日のCBD経皮ゲルで18.42%(n=62)、390mg/日のCBD経皮ゲルで14.03%(n=61)、及び偽薬で8.70%(n=63)であった。195mg/日(p=0.431)と、390mg/日(p=0.846)と、偽薬との間では、有効性において統計的な有意差はなかった。副次評価項目は、195mg/日、390mg/日及び偽薬の統計的有意差を示さなかった。50%の応答者率は、処置群全部にわたって類似しており、偽薬=23.8%、195mg/日=21%(p=0.414)及び390mg/日=16.4%(p=0.21)であった。
CBD経皮ゲルは、偽薬に匹敵する有害事象の発生及び活発な処置群間での臨床的有意差がないことで非常に十分に耐容性があった。CBD経皮ゲルの安全性特性は、第1相治験及び第2相治験からのデータと一致していた。CBD経皮ゲルを服用している患者におけるECG又は実験結果において、臨床的に有意な変化は何らなかった。加えて、CBD経皮ゲルは、皮膚耐容性が良好であり、皮膚の紅斑は最小限であった。
CBD経皮ゲルに対する臨床的に意味のある応答は、STAR1のベースライン期からの焦点性発作の低減によって測定されるように、CBD経皮ゲルを用いた処置の継続と相関している。CBD経皮ゲル(STAR1の間の3か月間で195mg/日、及びSTAR2における6か月間で390mg/日)を合計9か月間受けた患者は、65%の発作の低減の中央値に達した。CBD経皮ゲル(STAR1における3か月間及びSTAR2における6か月間で390mg/日)を服用した患者は、ベースラインからの発作の48%の中央値の低減に達した。加えて、CBD経皮ゲルは、9か月間の曝露を経て非常に十分に耐容性であることが示された。
STAR2臨床試験のプロトコルを修正して、観察された結果に基づいたCBD経皮ゲルの種々の用量の滴定を可能にした。この新たなプロトコルによって、医師は、195mg/日、390mg/日、585mg/日又は780mg/日でCBD経皮ゲルを処方することができる。修正されたプロトコルによって、医師は、CBD経皮ゲルの用量を上下に滴定することができる。
Claims (28)
- てんかんに罹患している対象における発作頻度を低減する方法であって、
有効量のカンナビジオール(CBD)を対象へ経皮的に投与することを含み、発作頻度が低減する、方法。 - 発作頻度が、30%低減する、請求項1に記載の方法。
- 発作頻度が、50%低減する、請求項1に記載の方法。
- 成人における焦点起始発作が低減する、請求項1に記載の方法。
- 焦点意識保持発作が低減する、請求項1に記載の方法。
- 焦点意識減損発作が低減する、請求項1に記載の方法。
- 全般強直間代発作をともなう焦点意識比較が低減する、請求項1に記載の方法。
- 対象が、高い発作頻度を有する、請求項1に記載の方法。
- てんかんが、薬剤抵抗性てんかんである、請求項1に記載の方法。
- レベチラセタム、カルバマゼピン、トピラマート、ラモトリギン、ラコサミド、クロナゼパム、バルプロアート、クロバザム、フェニトイン、エスリカルバゼピン(eslicarbaazepine)、及びオクスカルバゼピンからなる群から選択される少なくとも1つの抗てんかん薬を投与することを含む、請求項1に記載の方法。
- CBDが、(−)−CBDである、請求項1に記載の方法。
- 有効量のCBDが、毎日合計約195mg〜約780mgの間である、請求項1に記載の方法。
- 有効量のCBDが、分割日用量で195mgである、請求項1に記載の方法。
- 有効量のCBDが、分割日用量で390mgである、請求項1に記載の方法。
- 有効量のCBDが、分割日用量で585mgである、請求項1に記載の方法。
- 有効量のCBDが、分割日用量で780mgである、請求項1に記載の方法。
- 有効量のCBDが、97.5mgの単回使用のサシェ剤で提供される、請求項1に記載の方法。
- 有効量のCBDが、195mgの単回使用のサシェ剤で提供される、請求項1に記載の方法。
- 有効量のCBDが、390mgの単回使用のサシェ剤で提供される、請求項1に記載の方法。
- CBDが、ゲルとして製剤される、請求項1に記載の方法。
- CBDが、浸透性の亢進したゲルとして製剤される、請求項20に記載の方法。
- CBDが、単回日用量で投与される、請求項1に記載の方法。
- CBDが、2回日用量で投与される、請求項1に記載の方法。
- CBDが、合成CBDである、請求項1に記載の方法。
- CBDが、純CBDである、請求項1に記載の方法。
- 有効量のCBDを経皮的に投与すると、CBDを経口投与することに比べて、少なくとも1つの有害事象の強度が低減する、請求項1に記載の方法。
- 少なくとも1つの有害事象が、傾眠、精神刺激作用、肝機能、及び消化管関連有害事象からなる群から選択される、請求項26に記載の方法。
- 対象が、成人である、請求項1に記載の方法。
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